Development and validation of time-to-event models to predict metastatic recurrence of localized cutaneous melanoma.

BACKGROUND: The recent expansion of immunotherapy for stage IIB/IIC melanoma highlights a growing clinical need to identify patients at high risk of metastatic recurrence and, therefore, most likely to benefit from this therapeutic modality. OBJECTIVE: To develop time-to-event risk prediction models for melanoma metastatic recurrence. METHODS: Patients diagnosed with stage I/II primary cutaneous melanoma between 2000 and 2020 at Mass General Brigham and Dana-Farber Cancer Institute were included. Melanoma recurrence date and type were determined by chart review. Thirty clinicopathologic factors were extracted from electronic health records. Three types of time-to-event machine-learning models were evaluated internally and externally in the distant versus locoregional/nonrecurrence prediction. RESULTS: This study included 954 melanomas (155 distant, 163 locoregional, and 636 1:2 matched nonrecurrences). Distant recurrences were associated with worse survival compared to locoregional/nonrecurrences (HR: 6.21, P < .001) and to locoregional recurrences only (HR: 5.79, P < .001). The Gradient Boosting Survival model achieved the best performance (concordance index: 0.816; time-dependent AUC: 0.842; Brier score: 0.103) in the external validation. LIMITATIONS: Retrospective nature and cohort from one geography. CONCLUSIONS: These results suggest that time-to-event machine-learning models can reliably predict the metastatic recurrence from localized melanoma and help identify high-risk patients who are most likely to benefit from immunotherapy.

Unusual isolated cytomegalovirus cutaneous infections: A subtle histopathologic diagnosis with review of the literature.

Cytomegalovirus (CMV) infection is common and often self-limited. Reactivation results in a variety of disease presentations, especially in the setting of immunocompromise. While cutaneous manifestations of systemic CMV infection are rare, dermatologic manifestations of CMV are increasingly reported with a wide morphologic spectrum clinically. Three male patients, with untreated human immunodeficiency virus (HIV), penile lichenoid dermatitis treated with long-term topical and intralesional corticosteroids, and metastatic Merkel cell carcinoma on immune checkpoint inhibitor therapy, each presented with isolated cutaneous ulcers. The ulcers were located on the perianal skin, glans of the penis, and distal thumb. In each case, nonspecific histopathologic features were seen. However, very rare dermal cytomegalic cells with nuclear and cytoplasmic inclusions were present and highlighted with an immunohistochemical stain for CMV. Isolated ulcers due to CMV infection may occur in the setting of systemic or localized immunosuppression. A high index of suspicion is needed upon histopathologic evaluation, as few cytomegalic cells may be present and accurate diagnosis is crucial for prompt and appropriate clinical management.

Histopathologic clues to the etiopathogenesis of orbital inflammatory disease: Idiopathic, IgG4-related, neoplastic, autoimmune and beyond.

Orbital inflammatory diseases represent a heterogenous group of idiopathic, autoimmune-related, and sometimes neoplastic conditions with overlapping clinical and histopathologic features, as well as variable levels of IgG4-positive plasma cells detected within tissue biopsies. Some histopathologic features, especially in an appropriate clinical context, may point to a specific diagnosis in a given patient. Diagnoses of non-specific orbital inflammation, orbital inflammation related to autoimmune diseases such as granulomatosis with polyangiitis and IgG4-related disease, lymphoma, and xanthogranulomatous diseases are discussed, contrasted and illustrated.

A Rapidly Expanding Hemorrhagic BRAF-Mutant Orbital Atypical Glomus Tumor.

A healthy 32-year-old woman presented with the acute onset of left sided eye pain, upper eyelid fullness, and binocular diplopia during light weightlifting. Examination elevated intraocular pressure, proptosis, upper eyelid ptosis, and motility deficits. CT demonstrated a well-circumscribed, homogeneous-appearing extraconal mass in the superior left orbit. The patient underwent an urgent orbitotomy with the excision of a hemorrhagic mass. Histopathology showed a glomus tumor with atypical features and hemorrhagic infarction, best classified as having uncertain malignant potential. A B-Raf proto-oncogene V600E mutation was detected with immunohistochemistry, which suggests a more aggressive tumor behavior yet presents an opportunity for targeted primary or adjunctive therapy. This is the first reported case of a B-Raf proto-oncogene-mutant atypical glomus tumor arising in the orbit.

Melanoma Arising Beneath the Lateral Rectus Muscle in a Teenager With Ocular Melanocytosis: Possible Origin From Intrascleral Melanocytes.

Ocular melanocytosis is a well-established risk factor for choroidal melanomas but, despite its reported associations in the literature, it is infrequently discussed in relation to orbital melanomas. The authors describe a teenage patient with ocular melanocytosis who presented with an asymptomatic ipsilateral right orbital mass associated with the lateral rectus muscle. An exploratory orbitotomy revealed a lesion lightly adherent to the underlying sclera. Histopathology demonstrated a markedly atypical epithelioid melanocytic proliferation, bound by a thin rim of superficial sclera, implying an origin from intrascleral melanocytes, likely within an emissary canal. Next-generation sequencing identified GNAQ and NF1 mutations. The histopathology and molecular genetics designated the lesion as having a uveal melanoma-like profile, suggesting that it may behave as a choroidal melanoma. This case underscores the importance of the association between ocular melanocytosis and orbital melanoma and provides additional evidence for primary orbital melanoma etiopathogenesis.

"Demodicosis" Mimicking PreSeptal Cellulitis: Severe Periocular and Facial Inflammation Caused by "Normal" Skin Flora.

Due to their relatively high prevalence and commensalism, the pathogenicity of Demodex mites has been debated. Recent data, however, show Demodex to be associated with skin and ocular surface diseases such as rosacea, blepharitis, and keratitis. Here the authors report the first known case, to the best of the their knowledge, of Demodex infestation mimicking preseptal cellulitis in an adult human. A 29-year-old male bilaterally blind from advanced retinopathy of prematurity presented with a 2-month history of right-greater-than-left upper eyelid and periocular/cheek swelling, redness, and ocular discharge that did not resolve with oral antibiotics or oral steroids. Based on MRI findings, biopsies of the right lacrimal gland, right orbital fat, and right upper eyelid preseptal skin were obtained which revealed marked intrafollicular Demodex mite density and budding yeasts in the upper eyelid skin. This case serves to alert clinicians to this entity that may not otherwise be usually considered in ophthalmic clinical practice.

Distinguishing spheno-orbital metastatic prostate cancer mimicking a meningioma using novel 18F-PSMA PET/CT imaging.

A 78-year-old man presented with acute-onset left temporal pain, eyelid swelling, and double vision. Computed tomography (CT) demonstrated a left sphenoid wing mass with extra-osseous intra-orbital and intracranial extension, thought to be a typical sphenoid wing meningioma by the primary team. The patient was admitted for an urgent craniotomy, which was planned for the following day. However, upon consultation with ophthalmic plastic surgery, concern was raised for an alternative diagnosis given the atypical timeline, inflammatory changes, and uncharacteristic imaging findings of mixed lytic and sclerotic bony changes without hyperostosis on CT and extensive peri-lesional dural thickening and enhancement on magnetic resonance imaging. A serum prostate-specific antigen was elevated to 206 ng/mL. Subsequent positron emission tomography (PET)/CT using 18F-fluorodeoxyglucose radiotracer was negative for metastatic disease. A prostate-specific membrane antigen (PSMA) PET/CT was then obtained and demonstrated extensive metastases. An orbital biopsy revealed poorly differentiated prostatic adenocarcinoma. The significant incongruence between the standard PET/CT and PSMA PET/CT highlights the value of this novel advanced radiographic modality in narrowing the differential diagnosis and determining the extent of disease. Findings of widespread metastasis on the PSMA PET/CT ultimately helped to avoid a large, morbid neurosurgical intervention in this patient, allowing for a minimally invasive orbital biopsy to characterize the tumor for therapeutic targeting.

Pseudomonas species may appear strikingly filamentous in tissue sections: an important consideration for surgical pathologists and a reminder of the utility of modified silver impregnation methods.

Although tissue culture is the gold standard for diagnosing infection, histologic examination of surgically resected tissue can be a critical component in the diagnosis of tissue infection. The goal of this brief report is to alert surgical pathologists that Pseudomonas species can appear strikingly filamentous histologically and may somewhat mimic the appearance of filamentous bacteria, such Actinomyces or Nocardia, or thin fungal hyphae. A secondary aim is to raise awareness that Pseudomonas can sometimes only be identified histologically through the use of a modified silver impregnation method (Steiner stain). Five cases of filamentous Pseudomonas were encountered in three different surgical pathology subspecialities (ophthalmic pathology, cardiovascular pathology, and dermatopathology) over a 1-year period. All cases were of formalin-fixed, paraffin-embedded tissue, stained using hematoxylin & eosin (H&E) and multiple histochemical stains. Four cases grew Pseudomonas aeruginosa in culture and, in the fifth case, a nonaeruginosa species was detected using polymerase chain reaction-based methods. The markedly filamentous-appearing Pseudomonas organisms were identified in five different tissue sites: vascular graft, enucleation (whole eye) specimen, scleral biopsy, soft-tissue excision, and skin punch biopsy. In one of the five cases the organisms were seen on H&E, and in only two of the five were the organisms seen on Brown-Hopps stain. In all five cases, the organisms were identified on Steiner stain. It is therefore important to recognize that Pseudomonas can appear markedly filamentous, Pseudomonas or other bacterial infection is suspected, the surgical pathologist would be advised to employ the Steiner stain to most consistently detect the organisms.

Silicone Granulomas of the Eyelids-A Case Series Illustrating a Distant Migratory Phenomenon.

PURPOSE: Exogenous silicone has been reported to migrate to anatomic sights far from an initial injection or implantation site; this phenomenon has been rarely described in the ocular adnexa, especially in the eyelids. We document 3 additional cases of distant migration of silicone implanted elsewhere in the body to the eyelids and review the prior literature on this uncommon event. METHODS: A retrospective chart review of 3 patients was conducted along with analysis of diagnostic histopathology. A comprehensive review of the literature regarding dissemination or migration of silicone to the eyelids in patients with either silicone breast implants or silicone facial filler use was performed. RESULTS: Cases of silicone migrating to the eyelids from silicone breast implants and silicone-based facial filler are outlined in Tables 1 and 2, respectively. There are 4 total reports of women with silicone breast implants, including the 2 described here, with evidence of migration of silicone to the eyelid. Similarly, 5 cases of silicone-based facial filler with resultant migration of filler to the eyelids were identified, including 2 of the cases presented in this report (1 patient had both silicone breast implants and silicone facial filler). CONCLUSION: Silicone is chemically inert, but is known to travel throughout the body, causing a resultant foreign body response in tissue that can adversely affect even the eyelids. Silicone has a relatively characteristic histologic appearance and diagnosis of silicone granuloma highlights the importance of obtaining a thorough clinical history, particularly regarding prior cosmetic injections or breast enhancement surgery. Foreign material/foreign body granuloma is important to consider in patients with deep eyelid nodules of unclear etiology.

Clear Cell Syringoma of the Eyelids, a Distinctive Histopathologic Variant Associated with Diabetes Mellitus.

The authors describe the clinical and histologic findings of the clear cell variant of syringoma. Three adult female patients (age range 39-76 years old) were found to have multiple, flesh-colored lower eyelid papules, clinically consistent with syringomas, but histologically displaying abundant clear cell change. Two patients had known diagnoses of uncontrolled diabetes.

Primary vitreoretinal involvement and immunopositivity for BRAFV600E help distinguish metastatic from primary intraocular melanoma: a detailed histopathologic study of metastatic cutaneous melanoma to the eye.

OBJECTIVE: To evaluate the clinicopathologic characteristics of metastatic cutaneous melanoma to the eye and identify potential distinguishing characteristics from the more common primary uveal melanoma; particularly, tumour location within the eye, cytomorphology and immunohistochemical/specific molecular genetic features. METHODS: A retrospective observational case series using surgical enucleation and diagnostic vitrectomy cytologic specimens from seven patients with suspected intraocular melanoma, eventually diagnosed as metastatic melanoma, was conducted. Haematoxylin and eosin-stained sections of tumour and immunohistochemical (IHC) stains for BRAFV600E and Ki-67 were critically reviewed; BAP1 IHC was also evaluated in cases where additional tissue was available. Clinical imaging studies and medical records were reviewed. RESULTS: The majority of patients (86%) with metastatic melanoma have primary vitreoretinal (not uveal) involvement and epithelioid, highly malignant cytomorphology (100%); many (50%) harbour BRAFV600E mutations, a finding not seen in large cohorts of primary uveal melanoma. CONCLUSIONS: Characteristics favouring or defining metastatic intraocular melanoma over primary uveal melanoma include high-grade epithelioid cytology, predominant involvement of the vitreous cavity and/or retina, and presence of positive immunostaining for BRAFV600E.

Use of Cytokeratin 17 in the Differentiation Between Desmoplastic Trichilemmoma and Cutaneous Basal Cell Carcinoma.

ABSTRACT: Desmoplastic trichilemmoma (DTL) is a variant of trichilemmoma characterized by a prominent desmoplastic stroma that may mimic invasive carcinoma. These lesions typically show features of a conventional trichilemmoma at the periphery, surrounding dense hyalinized stroma with entrapped cords of tumor cells. On a small or superficial biopsy, DTL may pose a diagnostic challenge in distinguishing this benign adnexal neoplasm from invasive carcinoma, particularly basal cell carcinoma (BCC). We aimed to investigate whether the immunohistochemical expression of cytokeratin 17 (CK17) would be useful in the differentiation between DTL and BCC. CK17 is expressed in normal adnexal structures and has been shown to demonstrate strong staining in BCCs. Expression of CK17 was examined in 23 cases of DTL and 23 BCCs. An immunoreactivity score was assigned using the percentage of tumor cells staining with scoring as follows: 0, complete negativity; 1, < 15% tumor cells staining; 2, 15%-84% tumor cells staining; and 3, >85% staining. All cases of BCC scored as 3, whereas 18% of DTL scored as 3. The mean percent staining for CK17 was significantly higher for BCCs (97% of tumor cells) than DTLs (57% of tumor cells); P < 0.001 in the unpaired t test. The pattern of CK17 staining may also help differentiate between cases scoring 3. All BCCs showed strong diffuse staining throughout, whereas for those cases of DTL with a score of 3, the peripheral basaloid rim in the tumor lobules did not stain. CK17 is a useful adjunct in distinguishing DTL from BCC in small or superficial biopsy specimens.

PRAME Expression in Junctional Melanocytic Proliferations of the Conjunctiva: A Potential Biomarker for Primary Acquired Melanosis/Conjunctival Melanocytic Intraepithelial Lesions.

ABSTRACT: Conjunctival melanocytic proliferations are diagnostically challenging, often complicated by small specimen size, and are separated into 3 broad categories. The first group includes benign nevi and primary acquired melanosis (PAM) without atypia. The second group includes junctional melanocytic proliferations with a risk of progression to invasive melanoma (PAM with atypia). The last category is conjunctival melanoma, of which 65% of tumors arise in the setting of PAM with atypia. Preferentially expressed antigen in melanoma (PRAME) immunohistochemistry has been widely adopted to differentiate cutaneous nevi and melanoma. However, there are limited studies on its utility in the evaluation of conjunctival melanocytic proliferations with little data regarding its potential utility in stratifying PAM. Twenty-eight clinically annotated cases (14 PAM without atypia and 14 PAM with atypia) were retrospectively evaluated with PRAME/MART-1 duplex immunohistochemistry and were assigned the commonly used PRAME immunoreactivity score: 0 for no staining, 1+ for 1%-25% of cells positive, 2+ for 26%-50%, 3+ for 51%-75%, and 4+ for >75%. PAM without atypia showed low (0-3+) PRAME expression in 14 of 14 cases (100%). PAM with atypia showed strong and diffuse (4+) PRAME expression in 12 of 14 cases (86.7%). Seven of eight (87.5%) PAM with severe atypia, 4 of 4 PAM (100%) with moderate atypia, and 1 of 2 PAM (50%) with mild atypia showed 4+ PRAME expression. In addition, all 5 cases that recurred or progressed (all classified as PAM with atypia) showed 4+ PRAME expression. Although additional larger studies are needed, PRAME seems to be a useful adjunct in evaluating junctional melanocytic proliferations of the conjunctiva.

Lymphoma of the Lacrimal Sac: The Massachusetts Eye and Ear Experience With a Comparison to the Previously Reported Literature.

PURPOSE: To describe the frequency, clinical features, and histologic subtypes of biopsy proven lacrimal sac lymphomas, and to compare these results to the previously published literature. METHODS: A retrospective chart review was performed at a single institution from 2004 to 2017. Pathology reports, operative notes, and patients' medical charts were reviewed. RESULTS: Of 566 lacrimal sacs submitted for routine histopathologic evaluation, 16 cases of lymphoma were identified. All were low-grade, non-Hodgkin B-cell lymphomas, biopsied at an average age of 71 years. Thirteen patients (81.25%) had a pre-existing lymphoma diagnosis; the average interval between the diagnosis of systemic or nonocular adnexal lymphoma and lacrimal sac lymphoma was 7.9 years (range 2-26 years; median 5.5 years). Three cases of primary lacrimal sac lymphoma were identified. Histopathology showed 3 cases (18.75%) of follicular lymphoma, 3 (18.75%) of extranodal marginal zone lymphoma, and 10 (62.5%) of chronic lymphocytic leukemia/small lymphocytic lymphoma. Primary cases presented with epiphora and nasolacrimal duct obstruction, while secondary cases predominantly manifested as dacryocystitis. All lacrimal sac neoplasms were locally responsive (without local recurrence) to chemotherapy, radiation, or both. CONCLUSIONS: Lacrimal sac lymphoma is uncommon but should be suspected among patients with known lymphoma who develop dacryocystitis. In this series, primary lacrimal sac lymphoma most often presented as a mass or nasolacrimal duct obstruction. Chronic lymphocytic leukemia/small lymphocytic lymphoma was the most commonly identified cause of secondary lacrimal sac lymphoma. Distinguishing primary from secondary lacrimal sac lymphomas is important, as the extent of disease and histopathologic subtypes differ, which may affect patient management.

Wells Syndrome Presenting as Atypical Periorbital Cellulitis.

A 62-year-old man presented with diffuse, painless, left-sided preseptal edema, erythema, and woody induration extending to the left temple. The induration generated an orbital compartment syndrome with markedly elevated intraocular pressure necessitating lateral canthotomy and cantholysis. Although atypical for an infectious etiology, empiric broad-spectrum intravenous antibiotics were initiated with no improvement. A tissue biopsy demonstrated extensive perivascular and interstitial eosinophils with focal flame figures, and the patient was diagnosed with a severe hypersensitivity reaction or eosinophilic cellulitis (Wells syndrome). The disease process remitted rapidly upon initiation of oral prednisone. Wells syndrome is a rare inflammatory eosinophilic dermatosis, most often presenting in the limbs and trunk, with few reports of facial and periorbital involvement. This case highlights the importance of considering Wells syndrome in the differential diagnosis of atypical periorbital cellulitis that is nonresponsive to antibiotics and reviews the clinicopathologic nature of this disease.

Pathology of the Brain and the Eye in Severe Acute Respiratory Syndrome Coronavirus-2-Infected Patients: A Review.

BACKGROUND: Patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may present or eventually develop central nervous system and ophthalmic signs and symptoms. Varying reports have emerged regarding isolation of viral RNA from these tissue sites, as well as largely autopsy-based histopathologic descriptions of the brain and the eye in patients with COVID-19. EVIDENCE ACQUISITION: A primary literature search was performed in literature databases such as PubMed, Google Scholar, and Cochrane Library. Keywords were used alone and in combination including the following: SARS CoV-2, COVID-19, eye, brain, central nervous system, histopathology, autopsy, ocular pathology, aqueous, tears, vitreous, neuropathology, and encephalitis. RESULTS: The reported ophthalmic pathologic and neuropathologic findings in patients with SARS-CoV-2 are varied and inconclusive regarding the role of direct viral infection vs secondary pathology. The authors own experience with autopsy neuropathology in COVID-19 patients is also described. There is a particular paucity of data regarding the histopathology of the eye. However, it is likely that the ocular surface is a potential site for inoculation and the tears a source of spread of viral particles. CONCLUSIONS: Additional large postmortem studies are needed to clarify the role of SARS-CoV in the ophthalmic and neuropathologic manifestations of COVID-19.

Conjunctival Exophytic Schneiderian-type Papillomas: A Rare Occurrence.

Conjunctival papillomas are common tumors that exhibit an exophytic growth pattern, comprised of multiple filiform fronds of squamous epithelium that contain fibrovascular cores. The inverted (endophytic) variety of papilloma, often termed "Schneiderian," rarely occurs on the conjunctiva, with only 15 cases reported to date. Endophytic and exophytic papillomas are well described arising in the sinonasal Schneiderian epithelium where a low rate of malignant transformation may occur in the endophytic type; malignant transformation in exophytic sinonasal papillomas is exceedingly rare. The authors describe 2 cases of exophytic conjunctival papillomas with the morphology of a sinonasal or Schneiderian-type papilloma. Both were pink, sessile acquired growths in women in the sixth decade of life involving the inferior conjunctival fornix or nasal limbus. Nonkeratinizing squamous epithelium along with numerous goblet cells, intraepithelial mucinous cysts, and microabscesses were present. Immunohistochemistry showed reactivity for cytokeratin 7 and wild-type staining for p16 and p53, paralleling the findings in common conjunctival papillomas; both were also driven by low-risk human papillomavirus.

Lacrimal Gland Intravascular Micrometastasis From a Human Papillomavirus-Driven Anorectal Squamous Cell Carcinoma With a Review of Metastatic Disease to the Lacrimal Gland.

PURPOSE: To document a unique case of anorectal squamous cell carcinoma that was metastatic to the microvasculature of the lacrimal gland in a patient with human immunodeficiency virus and to review previously reported cases of metastases to the lacrimal gland. METHODS: Both a retrospective chart review and comprehensive literature review were performed. The unusual histopathologic pattern of the current case was illustrated with immunohistochemical studies (CD31, D2-40, pancytokeratin, p16, and p63) and in situ hybridization studies for high-risk human papillomavirus types 16 and 18. RESULTS: The authors describe the first case of metastatic anorectal squamous cell carcinoma to the lacrimal gland. Only 24 cases of metastatic disease to the lacrimal gland have been reported, the majority from breast carcinomas. The metastasis did not form a macroscopic lesions, instead was composed of microscopic intravascular and intraparenchymal tumor deposits, a subtle phenomena. Immunohistochemistry confirmed the presence of the intravascular neoplastic cells. p16 served as a surrogate marker for human papillomavirus-associated squamous cell carcinoma and was confirmed with in situ hybridization for human papillomavirus 16 and 18. This testing, combined with the clinical history, defined the diagnosis and confirmed human papillomavirus as the tumor driver. CONCLUSIONS: Metastases to the lacrimal gland remain rare, but clinicians and pathologists alike must be attuned to the possibility of subtle microscopic foci of tumor as a pattern of metastasis in scenarios without a discrete mass-forming lesion, as this may portend a poor prognosis.